viruses Review A Pandemic within Other Pandemics. When a Multiple Infection of a Host Occurs: SARS-CoV-2, HIV and Mycobacterium tuberculosis Carmen María González-Domenech 1,2,* , Isabel Pérez-Hernández 3, Cristina Gómez-Ayerbe 1,4, Isabel Viciana Ramos 1,4, Rosario Palacios-Muñoz 1,4 and Jesús Santos 1,4 1 Clinical Research in HIV Infection, Endovascular Infection and Bacteriemia, Biomedical Research Institute of Malaga (IBIMA), 29010 Malaga, Spain; [email protected] (C.G.-A.); [email protected] (I.V.R.); [email protected] (R.P.-M.); [email protected] (J.S.) 2 Department of Microbiology, Faculty of Sciences, University of Malaga, 29071 Malaga, Spain 3 Internal Medicine Service, Melilla Regional Hospital, 52005 Melilla, Spain; [email protected] 4 Infectious Diseases and Clinical Microbiology Unit, Virgen de la Victoria Hospital, 29010 Malaga, Spain * Correspondence: [email protected] Abstract: By the middle of 2021, we are still immersed in the coronavirus disease 2019 (COVID- 19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The concurrence of this new pandemic in regions where human immunodeficiency virus (HIV) and tuberculosis (TB) infections possess the same epidemiological consideration, has arisen concerns about the prognosis, clinical management, symptomatology, and treatment of patients with triple Citation: González-Domenech, C.M.; infection. At the same time, healthcare services previously devoted to diagnosis and treatment of Pérez-Hernández, I.; Gómez-Ayerbe, TB and HIV are being jeopardized by the urgent need of resources and attention for COVID-19 C.; Viciana Ramos, I.; patients. The aim of this review was to collect any article considering the three conditions (HIV, TB, Palacios-Muñoz, R.; Santos, J. A and SARS-CoV-2), included in PubMed/Medline and published in the English language since the Pandemic within Other Pandemics. beginning of the COVID-19 pandemic. We focused on detailed descriptions of the unusual cases When a Multiple Infection of a Host describing the three co-infections. Eighty-four out of 184 publications retrieved met our inclusion Occurs: SARS-CoV-2, HIV and criteria, but only three of them reported cases (five in total) with the three concomitant infections. Mycobacterium tuberculosis. Viruses The clinical evolution, management, and therapy of all of them were not different from mild/severe 2021, 13, 931. https://doi.org/ cases with exclusive COVID-19; the outcome was not worse either, with recovery for the five patients. 10.3390/v13050931 Cases of patients with COVID-19 besides HIV and TB infections are scarce in literature, but studies Academic Editor: Herve J A Fleury deliberately embracing the triple infection as a priori inclusion criterion should be carried out in order to provide a complete understanding of joint influence. Received: 15 April 2021 Accepted: 16 May 2021 Keywords: SARS-CoV-2; COVID-19; HIV; tuberculosis; coinfection; triple-infection Published: 17 May 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in 1. Introduction published maps and institutional affil- According to UNAIDS global human immunodeficiency virus (HIV) statistics, there iations. were over 38 million people worldwide living with HIV (PLWHIV) at the end of 2019. Most of cases are concentrated in sub-Saharan Africa; among the most devastated countries by HIV epidemic, South Africa possesses the highest number of PLWHIV [1]. Untreated HIV replication causes a wide range of immunological dysfunction, with a progressive loss of Copyright: © 2021 by the authors. CD4(+) T cell and B cell functionality, leading to an increased risk of opportunistic infections Licensee MDPI, Basel, Switzerland. and carcinogenic events [2–4]. In this context, pneumonia by different pathogens was a This article is an open access article leading cause of morbidity and mortality before the institution of antiretroviral therapy distributed under the terms and (ART) [5]. Afterwards, the implementation of ART from the mid-1990s substantially conditions of the Creative Commons improved HIV patients’ quality of life and life expectancy to such an extent that they are Attribution (CC BY) license (https:// currently close to those for individuals without HIV infection [6–8]. However, far from creativecommons.org/licenses/by/ being an eradication treatment, ART must currently be taken for life. As well-known and 4.0/). Viruses 2021, 13, 931. https://doi.org/10.3390/v13050931 https://www.mdpi.com/journal/viruses Viruses 2021, 13, 931 2 of 13 presently unsolved, there exists a main obstacle for a functional or sterilizing cure of the HIV infection: its viral latency and ability to rebound viremia following ART interruption. HIV possesses plenty of molecular mechanisms targeted to establish and maintain a latent infection, and, as a consequence, a chronic immune disorder (for a review see [9–11]). Besides the effects of HIV-induced persistent systemic inflammation and the impact of long-term ART on respiratory immune response, the lung is a known reservoir for HIV, so this organ may be exposed to an increased frequency of other pulmonary diseases [12]. For its part, tuberculosis (TB) is an ancient but still present human disease caused by Mycobacterium tuberculosis (MTB), and almost exclusively transmitted through the air [13,14]. Worldwide, TB was considered in the global top 10 causes of death at the beginning of this century, falling from 7th place in 2000 to 13th in 2019, with a 30% reduction in global deaths. Nevertheless, it remains among the top 10 causes of death in the African and South- East Asian regions. According to World Health Organization (WHO), over 10 million people fell ill with TB worldwide, and almost one million and a half people died from TB (including 208,000 people with HIV) in 2019. About half of the new TB cases occurred in the South-East Asian region (44%), followed by the African region (particularly in sub-Saharan Africa), with a quarter new cases (25%), and the Western Pacific with approximately a fifth (18%), according to Global Health Observatory data repository (2020). Two thirds of the number of cases are concentrated in just eight countries, with India leading the count, followed by Indonesia, China, the Philippines, Pakistan, Nigeria, Bangladesh and South Africa [15]. Pulmonary presentation is the most common, although the mycobacteria can spread to other organs or systems (such as skin, liver, central nervous, musculoskeletal and reproductive systems) through the hematogenous route [16,17]. Somehow similar to a treatment-controlled HIV patient, with the virus concealed itself in CD4+ T cells, there is a latent TB infection characterized by the pathogen lying dormant inside the lungs, without causing destruction of organs [13,14]. Anyway, PLWVIH and also with a latent TB infection present a higher risk of progressing to active disease, with a predominant extrapulmonary manifestation [15,16,18]. Thus, HIV and TB may represent a lethal tandem. Finally, at the time of writing this review, we are still immersing in the pandemic of coronavirus disease 2019 (COVID-19). The etiological agent is a member of Coronaviridae (CoV) family, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses basing on phylogenetic analysis [19]. This family comprises four major genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus; the two former, the Alpha and Beta-CoVs, have the ability to infect humans [20,21], and cause a range of illnesses, from the common cold to a severe acute respiratory tract infection. The first reported case emerged in Wuhan, Hubei Province, China, in December 2019, and soon turned into a global threat, because of its viral infectivity and its permanent within-host evolution. Since then, the virus has caused over 108 million confirmed cases and almost 2.4 million deaths worldwide at the time of writing (middle of February 2021) [22]. The dominant route of transmission for SARS-CoV-2 is airborne aerosol/droplet, but transplacental transmission is also described [23,24]. After entering the lungs by inhalation, SARS-CoV-2 activates immune system, cytokines, and other pathogen- resistance mechanisms. As previously exposed for HIV, acute infection for SARS-CoV-2 is also associated with lymphopenia, and the severe decline of CD4+ T cell counts and B cell dysfunction in COVID-19 patients have been linked to poor clinical outcomes [25–31]. The dynamic of lymphocyte subsets changes in the course of both infections are not comparable though, because SARS-CoV-2 chronification is currently ruled out, unlike HIV [32]. In light of the above, the concurrency of a new pandemic within two other pandemics has jeopardized health care providers for TB and HIV patients. Thus, resources achieved over a long period for control of HIV and TB infections are now being redirected to COVID- 19. This situation is dramatically evident in many African countries, especially in South Africa [33–36]. In this review, we collected and summarized any research or scientific thought si- multaneously considering these three conditions, especially when concerned impact on Viruses 2021, 13, 931 3 of 13 public health. We sought studies reporting unusual cases of a triple infection with My- cobacterium tuberculosis, HIV, and SARS-CoV-2. Differences and similarities in clinical management, respiratory therapy, symptomatology, or outcomes were searched and com- pared to